www.HIMSSConference.org

#PrecisionHIT

FEBRUARY 11, 2019

ORLANDO, FL

Moving Genomics to General Practice

Nephi Walton MD MS FACMG

Genomic Medicine Institute

MyCode Return of Results Program

• 200,000+ consented

• 140,000 sequenced

• 1000+ results

returned

• Return results for all

ACMG reportable

conditions

Precision Health Pilot

• Preventative measure

• 1000 patients sequenced as a routine part of clinical care

• Offered through patient’s primary care provider

• Return results for all ACMG reportable conditions

Genetics by the Numbers

• 46 Chromosomes

• ~20,0000-23,000 genes

• ~3 billion base pairs in the human genome

• BRCA2 is 83,736 base pairs

• Every time you have child they will incur 100 to 200 new mutations

• Mutation rate increases with the age of the father

Genetic mutations do not usually give you super powers

What your genes can tell physicians

• What diseases you are likely to develop

• How you will react to medication

• How you will respond to infectious diseases

• How you will behave

• How you will sleep

• What you eat

What is Medical Genetics/Genomic Medicine

• Started in the late 1940s

• Did not require an MD – PhDs were often practitioners

• Dysmorphologists – Syndrome identification

• Familial risk identifiers

We did not even know how many chromosomes we had until 1956

First disease gene mapped in 1983

Pop Quiz! -

In what decade was the following statement printed?

“Of all the applications of medical genetics, the one

potentially most valuable is in the field of

preventative medicine.”

Pop Quiz!

In what decade was the following statement printed?

“Of all the applications of medical genetics, the one

potentially most valuable is in the field of

preventative medicine.”

Answer: 1946

The Role of a Clinical Geneticist

• Diagnosis

• Management

• Prevention

• Risk Assessment

• Counseling

Challenges in Clinical Genetics

• More than 6000 known genetic disorders

• Nationwide shortage of clinical geneticists

• Getting more referrals from specialists

• Shortage of genetic counselors

Challenges in Clinical Genetics

• Healthy people getting direct to consumer tests

• – MTHFR challenge

• Poor reimbursement for testing and services

• Uncertainty in classification of variants and diagnosis

• Poor access to data that is crucial in our field

• Up to one year wait times to see a geneticist

Physicians outside of clinical genetics are not

prepared to understand, deliver or manage

genetic test results

Systems that allow physicians access to quick and

accurate knowledge about genetic conditions are the

only way to solve this information overload

No one can acquire and maintain the knowledge to

diagnose and manage over 10,000 diseases.

Genomic medicine will move from a specialty

which did not even require an MD degree to

become an integral part of practice that is

required of everyone with an MD degree

Found to have a pathogenic variant in BRCA1

Elected to have a bilateral mastectomy

Discrepancies in Variant Classification Between 9 Laboratories

Amendola, Laura M. et al. “Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical

Sequencing Exploratory Research Consortium.” American Journal of Human Genetics 98.6 (2016): 1067–1076. PMC. Web. 8 June

2017.

Concordance of Variant Classification for BRCA1 and BRCA2

Gradishar William.et al. “Clinical Variant Classification: A Comparison of Public Databases and

a Commercial Testing Laboratory.” Oncologist. 2017 Apr 13. pii: theoncologist.2016-0431. .

BRCA1 and BRCA2 are two of the

most well studied genes in the

Human Genome…

AND WERE EVEN SCREWING

THOSE UP!

Also Keep in mind the people

classifying these variants are the

“experts” not general practice

physicians

Elisha Cooke-Moore vs Curry County Health

Elisha Cooke-Moore vs

Curry County Health

Bilateral mastectomy and

hysterectomy based on

Incorrect interpretation of

a genetic testing report

by clinician

1.8 Million dollar lawsuit

The discordance in variant

classification we have now is

primarily based on testing done

on people with disease

When you start testing healthy

people it’s a completely different

ball game!

FGFR3 Mutation - Achondroplasia

Exome Sequencing

Now a common clinical test

Reports on the expressed portion of the human genome

Generates data on all your expressed genes

Resulting data is 6-8 Gigabytes of crucial health information

What does the physician get?

Genomic Data Life Cycle

Sequencing is performed on one individual

Exome generates 6 to 8 GB of data

Whole genome generates 100 to 200 GB of data

Data is processed to produce a list of candidate genes changes

Further refined to a list of reportable variants put into a PDF

So what happens to the other 6GB to 200GB of data?

MRI Analogy

PACS System for Genomics

Data is too large for EHR data structures

Different kind of data requires a specialized viewer

Frequently changes – new data added

Requires specialist interpretation

May be useful for any physician to view especially at point of care

Integration of genomic data into the EMR for

patient management and decision support is

crucial to enabling general practice

physicians to practice genomic medicine

Summary of Challenges

• No way to store genetic data

• Clinical Genetics workforce will not scale to handle sequencing everyone

• No way to utilize genetic data in a clinical workflow

• Clinicians outside genomics not equipped to manage genetic testing results

Genetic Data – What to Store

1. Discrete Variants with Known Health Related Effects

1. Point Mutations, Indels

2. Copy Number Variants

2. Filtered Data

1. VCF

3. Raw Data

1. BAM, FastQ

Genetic Data – Where to Store

1. In EHR

2. In External Database linked to EHR

Discrete Variants

Currently reported as in a PDF

Workarounds include creating lab values that store variants

Only in past year has ability to store discrete variants been available

Getting Genetic Variants into the EHR

Epic has recently implemented “Genomic Indicators”

Will allow for clinical decision support around genomic variants

Gives genomics a home in the EHR – finally a place to put the data

Consortium for Agile Genomics – Getting Data From The Lab

HOLD UP!!!!

PDF from the lab ok to put into the system automatically

Discrete variant information as a genomic indicator – NOT OK

Why?

Bad Things Can and DO Happen

Case

• Patient in her 20s evaluated for connective tissue disease

• Clinically evaluated as hypermobile EDS

• Aortopathy panel sent

• VUS in gene for Loeys Dietz

• Cardiac MRI normal

Case – continued

• Patient seen by Ob/Gyn provider

• Provider sees genetic test

• Assigns diagnosis of Loeys Dietz in Epic

• Patient instructed that she MUST have a C-section

• Schedules monthly echocardiogram

• Patient calls genetics department

Providing too much information or too little…

Providing information that could be used the wrong way potentially exposes

the patient to unnecessary and potentially harmful action.

Hiding potentially useful information prevents patient from receiving the

appropriate action.

Where is the balance?

If malpractice is any indication…

Only a handful of cases regarding taking action because of wrong

interpretation.

Versus….

57% of all genomic medical malpractice cases could have been avoided if

genetic testing had been performed

Pharmacogenomics

New clinical exome laboratory offers PGx variants as option to patient.

General response - Yay!

My response – Uh Oh!

Multiple patients with pharmacogenomic results

• Who counsels the patient

• Is there a liability associated with not acting on results

• How do physicians find the report?

The rest of the DATA!

Which data is used?

• Raw Data

• Filtered Data

• Annotated Data

• Copy number call from exome/genome

Storing – “The rest of the data”

No place to store VCF files

No place to store discrete phenotypic information

A Genotype- Phenotype Archiving and Communication System (GPACS)

NIH SBIR grant in partnership with PhenoSolve (SimulConsult)

Grant Number NIH 1R43HG010322-01, PI: Segal, MM

GPACS

Phenotype Builder

Extracts phenotypic elements from free text and ICD10 codes

Builds phenotypic profile of HPO terms

Stores HPO terms in GPACS

We Have Genetic Data in the EHR – Now What?

Make sure genetic data is used accurately/effectively

• Diagnosis

• Clinical Decision Support

• Information Delivery to Providers

• Information Delivery to Patients

• Take Actions

Use of Genomic Information in Clinic - Simulconsult

eMERGE PGx

Clinical Decision Support built for

• CYP2C19 and Clopidogrel

• SLCO1B1 and Simvastatin

Delivering Information to Patients and Providers

• Working with Epic to implement this with genomic indicators

• Infobutton will reside next to the genomic indicator

• Provides information related to gene or variant

Compass/Gene Report

• HL7 compliant web service

• Activated through InfoButtons or

direct web-link

• Delivers different information based

on user - patient vs provider

• Delivers information specific to

variant, sex, and age

Implementation of Chatbots

Partnership with Clear Genetics

Use Chatbots for:

• Consenting patients

• Following up on test results

• Patient questions

• Cascade testing

•Chatbot work by Amy Sturm and Tara Schmidlen

Consent Chatbot

Patient Follow-Up Chatbot

Family Sharing Tool

Cascade Chatbot

Smart FAQ

What’s Next?

• How do we integrate all genomic information into the workflow?

• Which variants do we include and who decides?

• When working outside an ”expert” whose consensus guidelines are used?

• How can we effectively use information in real-time to impact patient care?

Acknowledgements

Geisinger

• Marc Williams

• Darren Johnson

• Bruce Levy

• Dean Parry

• Jordan Olson

• Bonnie Spandra

• Rebecca Pulk

• Chancey Christenson

• Amy Sturm

• Tara Schmidlen

University of Nebraska

• Scott McGrath

Simulconsult

• Michael Segal

• Lynn Feldman

HPO

• Peter Robinson

Epic

• Jordan Dantas

InfoButtons

• Guilherme Del Fiol

HL7/FHIR

• Gil Alterovitz

• Grant Wood

QUESTIONS?